Atherosclerosis is the leading cause of mortality in the western world. HDL, the levels of which are inversely correlated with the risk of atherosclerosis, exerts its protective effect in large part through its ability to mobilize cholesterol from peripheral cells and to stimulate reverse cholesterol transport to the liver. Atherosclerosis and inflammation share many common features and the atherosclerotic process exhibits characteristics of chronic inflammation. Inflammation significantly alters HDL structure, composition and levels, but the underlying mechanisms and the consequences of such modifications are not understood. In studying the impact of HDL on atherosclerosis it is therefore critical to understand how such HDL modifications, that can result both systemically and within the microenvironment of the atherosclerotic lesion, influence HDL metabolism and its role in cholesterol transport. Inflammatory modifications in HDL may also alter the protective effect of HDL in neutralizing the inflammatory effects of bacterial lipopolysaccharides. Inflammation and the acute-phase response results in a marked induction of acute phase proteins including serum amyloid A (SAA), which becomes a major HDL apolipoprotein. Recently, we identified two Class B scavenger receptors, SR-BI and CD36, as high-affinity receptors for SAA and also showed that SAA promotes cellular cholesterol efflux. Further, SR-BI and CD36 were shown to efficiently take up SAA into cells, a process that may be important in the function and metabolism of SAA. In this proposal we will examine the overall hypothesis that HDL cholesterol transport by Class B scavenger receptors is significantly altered during inflammation through the effects of acute phase proteins and modifications in HDL structure. Aim 1 will examine the hypothesis that the Class B scavenger receptors mediate the cellular uptake and catabolism of SAA. Studies will investigate the roles of SR-BI and CD36 in the cellular uptake, recycling and degradation of SAA in hepatocytes and macrophages. Aim 2 will determine how SAA and HDL remodeling during inflammation impacts HDL cholesterol transport by Class B scavenger receptors. Studies will investigate how SAA and acute phase modifications of HDL influence SR-BI-dependent cholesterol efflux from hepatocytes and macrophages and SR-BI-mediated selective lipid uptake into hepatocytes. Aim 3 will test the hypothesis that Class B scavenger receptors and SAA regulate the LPS-induced inflammatory response. Studies will examine the roles of SR-BI and CD36 in LPS- and LTA-induced inflammation and the modulating effects of SAA. These studies are expected to provide greater understanding of how inflammation influences the protective function of HDL.